The reproductive system of all animals, including humans, is sensitive to availability of nutrients, fat reserves, and metabolic hormones. The brain, particularly the hypothalamus and brainstem, integrates these metabolic signals and gates the activity of the neuroendocrine reproductive axis to optimize reproductive success. Precisely how the brain accomplishes this responsibility remains poorly understood. A newly discovered molecule, galanin-like peptide (GALP), may play a pivotal role in this process. GALP is only expressed in the arcuate nucleus and median eminence of the hypothalamus, which are nodal points for integration of metabolism and reproduction. Work from our laboratory and others has shown that GALP neurons are regulated by the metabolic hormones leptin and insulin and that GALP administration reduces food intake and stimulates gonadotropin secretion. These observations suggest that GALP neurons serve as part of the hypothalamic circuitry linking the regulation of body weight to reproduction; however, beyond these observations, we understand little about either GALP's physiological importance or its regulation. We propose to use physiological, pharmacological, neuroanatomical, in vivo cDNA targeting, microarray, and other molecular biological techniques to reveal the functional significance of GALP in the neuroendocrine reproductive axis. Our primary aims are 1) to reveal the functional significance of GALP by examining the phenotype of transgenic mice having a deletion of the GALP gene; 2) to explore the role of GALP in mediating the effects of leptin and insulin on the reproductive system by examining the effects of centrally administered GALP in mice beating deficiencies in leptin or insulin signaling; 4) to determine whether the effects of GALP are mediated by either galanin receptors or specific GALP receptors; 5) to evaluate the interaction between neuropeptide Y and GALP neurons in the arcuate nucleus; 6) to tease out the molecular mechanisms by which leptin, insulin, and peptide YY act on GALP neurons; and 7) to learn the identity and significance of downstream targets of GALP projections in the brain. Establishing the physiological effects of GALP and learning about the molecular physiology of GALP neurons and the basic circuitry that couples GALP to other neuronal systems are fundamental steps toward the goal of understanding GALP's functional role in the orchestration of the neuroendocrine reproductive system. This knowledge will hopefully lead to a better understanding of certain human diseases and disorders, such as precocious puberty, hypothalamic amenorrhea and polycystic ovarian disease, and provide an enlightened path towards their treatment.
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